This invention relates to methods of treating patients afflicted with inflammatory skin diseases, including acne, rosacea, eczema, atopic dermatitis, psoriasis and oily skin.
Acne is the most common skin disease. Epidemiologic data suggest that up to 80% of individuals may be affected. Men and women develop acne about equally, and the onset of the disease typically occurs at age 10-14 years and regresses by age 20-25 years. In some patients acne persists into fourth or fifth decade of life (persistent acne). The clinical spectrum of acne ranges from mild manifestations (e.g., a few comedones (acne lesions) with occasional inflamed papulopustules to “clinical” acne in more severe cases) to severe inflammation and abscess formation on the face or upper trunk. Follicular rupture may follow leading to a foreign body reaction including abscesses, fistulas and systemic signs of inflammation (acne conglobata).
Increased sebum production, which is believed to be regulated by androgens is thought to be one of the main causes of acne (seborrhea) development. A further prerequisite for developing acne is a disturbed follicular keratinisation leading to hyperkeratosis. Factors responsible for follicular hyperkeratosis include the following: localized, follicular linolic acid deficiency, comedogenic sebum components, changes in the lipid composition of sebum, bacterial metabolites and mediators of inflammation.
Propionibacteria (Propionibacterium acnes) are the dominant bacteria in hair follicles. These bacteria prefer micro-aerobic or anaerobic conditions and preferentially colonize regions with high sebum production. A four log higher concentration of propionibacteria is found in 11-20 year olds with acne compared to 11-20 year olds without acne. Bacterial lipases release irritative and pro-inflammatory free acids and other potentially pro-inflammatory bacterial metabolites such as proteases, hyaluronidases and chemotactic factors. Metabolites of propionibacteria induce follicular and perifollicular inflammation, especially due to chemotactic substances. Other immunological and inflammatory factors play also a role in the development and course of acne (e.g., toll-like receptor 2, IL-1, IL-8, LTB4, PPAR alpha).
There are a number of topical as well as systemic treatment options available for acne. Topical treatments for acne include: Retinoids, which normalise follicular keratinisation; Benzoylperoxide (BPO), which is an anti-bacterial agent that reduces Propionibacterium acnes (P. acnes) within the follicle; and topical antibiotics with an antibacterial effect. Systemic treatment options for acne include antibiotics. Systemic treatment options also include hormones for female patients.
Rosacea is a common, chronic cutaneous inflammatory disease, primarily of the facial skin. It is common in the third and fourth decade of life, peaking at the age of 40 and 50 years. The causes of rosacea have not yet been identified. Facial vascular reactivity, dermal connective tissue structure or composition, pilosebeaceous structure, microbial colonization and a combination of factors that alter the cutaneous response to rosacea trigger factors, respectively, are seen as major pathogenic mechanisms. Important trigger factors among others appear to be hot or cold temperature, sunlight, wind, hot drinks, spicy food, alcohol, exercise, emotions, and topical irritants which lead to flushing and blushing. Early stage rosacea is characterized by persistent erythema and teleangiectasia, predominantly of the cheeks, frequently followed by papules and papulopustules. In later stages, diffuse hyperplasia of connective tissue and sebaceous glands may occur. This can cause a hypertrophy of the nose, a so-called rhinophyma. Rosacea occurs in stages and may affect the eyes, most commonly resulting in blepharitis and conjunctivitis. Rosacea may occur in areas other than the face, such as retroauricular areas, as well as on the neck, chest, back and scalp. The clinical appearance of rosacea may be similar to acne, but, in contrast, rosacea is not a primary follicular disease.
Oral tetracycline antibiotics, such as tetracycline, doxycycline, and minocycline, and topical antibiotics, such as metronidazole, which are used in acne, are also a treatment option for rosacea and are used to relieve papules, pustules, inflammation and some redness.
Eczema is a general term encompassing various inflamed skin conditions such as atopic dermatitis, allergic contact dermatitis and occupational dermatitis.
Atopic dermatitis is a pruritic that typically starts in early infancy (although an adult-onset variant is recognized). Atopic dermatitis is characterized by pruritus, eczematous lesions, xerosis (dry skin), and lichenification (thickening of the skin and an increase in skin markings).
Atopic dermatitis results from complex interactions between genetic susceptibility genes resulting in a defective skin barrier, defects in the innate immune system, and heightened immunological responses to allergens and microbial antigens. The dysfunction of the barrier is caused by downregulation of cornified envelope genes (fillagrin and loricrin), reduced ceramide levels, increased levels of endogenous proteolytic enzymes, and enhanced transepidermal water loss. Disturbance of the barrier may also be caused by soaps and detergents and/or by exposure to exogenous proteases from house dust mites and Staphylococcus aureus. This is worsened by the lack of certain endogeneous protease inhibitors in atopic skin. These epidermal changes likely contribute to increased allergen absorption into the skin and microbial colonization. Current thinking is that microbial superantigens play a major role; they can more easily penetrate into the viable skin layers via the disturbed barrier and induce an influx of T cells (predominantly activated memory T cells suggesting previous encounter with antigen) with occasional macrophages.
Pruritus is a prominent feature of atopic dermatitis, manifested as cutaneous hyperreactivity and scratching following exposure to allergens, changes in humidity, sweating, and low concentrations of irritants. The mechanisms of pruritus are poorly understood; however, it is believed that inflammatory cells play an important role. There is an itch-scratch cycle. Repetitive scratching activates areas in the prefrontal cortex and orbifrontal cortex. This may explain the hedonic and compulsive components of scratching and may be associated with release of endogenous opioids. Repetitive scratching in atopic dermatitis causes secretion of neuropeptides and opiates that may further augment the vicious itch-scratch cycle.
Psoriasis is a polygenetic hereditary multifactor inflammatory skin disease of unknown pathogenesis, which may be influenced by a number of environmental factors. There is a strong genetic basis leading to complex alterations in epidermal growth and differentiation and multiple biochemical, immunological, and vascular abnormalities, and a poorly understood relationship to nervous system function. The pathogenesis of psoriasis is rather complex involving local and systemic factors. At present, the abnormal epidermal hyperproliferation is regarded as a secondary phenomenon following T-lymphocyte mediated autoimmune reaction. It has also been reported that immunological reaction to Streptococcus species may also play a role. Epidermal proliferation in lesional skin is characterized by increased recruitment of cycling cells from the resting G0 population. In contrast to older data, cell cycle times in the psoriatic lesion are essentially normal. In particular, the suprabasal compartment is characterized by expression of molecules that are absent or have restricted expression in normal skin. In primary keratinocyte cultures, soluble factors from CD4+ T-lymphocyte clones derived from psoriatic plaques promote proliferation of the psoriatic CD29+ keratin-10 subpopulation, whereas CD29+ keratin-10 keratinocytes from normal subjects failed to have such a growth response to soluble factors from the same T cell clones. This suggests that a subpopulation of epidermal cells derived from psoriatic plaques do respond abnormally to T-lymphocyte clones from psoriatic plaques.
Oily skin is due to excessive sebum production by sebaceous glands. Excessive sebum production may be caused by hormonal imbalances during pregnancy and menopause, heredity, diet, birth control pills, cosmetics use or humidity and hot weather or diseases such as Morbus Parkinson.
Excess sebum produces surface oiliness, blocks pores, provides nourishment to bacteria that live upon the skin (P. acnes) and contributes to acne flare-ups.
Impetigo contagiosa is a superficial bacterial skin infection most common among school children. People who play close contact sports such as rugby and wrestling are also susceptible, regardless of age. Impetigo is not as common in adults. It is highly contagious and also known as school sores. It is primarily caused by Staphylococcus aureus and by Streptococcus pyogenes. Impetigo generally appears as honey-colored scabs formed from dried serum, and is often found on the arms, legs, or face. The infection is spread by direct contact with lesions or with nasal carriers. The incubation period is 1-3 days. Dried streptococci in the air are not infectious to intact skin. Scratching may spread the lesions. Good hygiene practices can help prevent impetigo from spreading.
Subtypes of impetigo contagiosa are bullous impetigo and ecthyma. Bullous impetigo primarily affects infants and children younger than 2 years. It causes painless, fluid-filled blisters—usually on the trunk, arms and legs. The skin around the blister is usually red and itchy but not sore. The blisters, which break and scab over with a yellow-colored crust, may be large or small, and may last longer than sores from other types of impetigo. Ecthyma is a more serious form of impetigo in which the infection penetrates deeper into the skin's second layer, the dermis. Signs and symptoms include:                Painful fluid- or pus-filled sores that turn into deep ulcers, usually on the legs and feet        A hard, thick, gray-yellow crust covering the sores        Swollen lymph glands in the affected area        Little holes the size of pinheads to the size of pennies appear after crust recedes        Scars that remain after the ulcers heal        
For the treatment of impetigo contagiosa and its subtypes topical or oral antibiotics are usually prescribed. Mild cases can be treated with bactericidal ointment, such as fusidic acid, mupirocin, chloramphenicol, clioquinol or neosporin. More severe cases require oral antibiotics, such as dicloxacillin, flucloxacillin or erythromycin. Alternatively amoxicillin combined with clavulanate potassium, cephalosporins (1st generation) and many others may also be used as an antibiotic treatment. The mentioned medicaments may be used in the form of any of pharmaceutically acceptable salts, optical isomers, diastereomers, enantiomers, hydrates, and pharmaceutically acceptable salts thereof.
There are various disadvantages associated with the available treatments for inflammatory skin diseases.
Retinoids are an available treatment options for acne. Clinical improvement following treatment with Retinoids typically requires several weeks, and Retinoids are known to possess teratogenic properties. Retinoids may also be irritants. Onset of action is quite rapid with BPO and resistance to P. Acnes has not been reported; however, BPO is a bleaching agent and, therefore, whitening of clothing and bedding may occur. Furthermore, BPO is a potential irritant and may act as a mutagen. The number of topical antibiotics currently used has led to high percentage of resistance. Thus, a need exists for improved treatments for acne and other inflammatory skin diseases.
1-Amino-alkylcyclohexane derivatives such as neramexane (also known as 1-amino-1,3,3,5,5-pentamethylcyclohexane) have been found to be useful in the therapy of various diseases especially in certain neurological diseases, including Alzheimer's disease and neuropathic pain. 1-Amino-alkylcyclohexane derivatives such as neramexane are disclosed in detail in U.S. Pat. Nos. 6,034,134 and 6,071,966, the subject matter of which patents is hereby incorporated by reference.
Surprisingly, it has now been found that 1-amino-alkylcyclohexane derivatives such as neramexane are also suitable for treating inflammatory skin diseases.
The beneficial impact of 1-amino-alkylcyclohexane derivatives such as neramexane on sebocytes also contributes to the effective treatment of inflammatory skin diseases including acne, rosacea, eczema, atopic dermatitis, psoriasis and oily skin. The impact on proliferation and/or differentiation of sebocytes and thus the ability to reduce lipid production allows for regulation of sebum secretion. In addition to overall sebum regulation, the composition of sebum may also be influenced, leading to normalization of the pathophysiological phenotype of the diseased hair-follicle.
Patients with inflammatory skin diseases often exhibit a disturbed cutaneous barrier function. 1-Amino-alkylcyclohexane derivatives such as neramexane may improve the cutaneous barrier function and block the delay of barrier recovery which results in a positive effect on homeostasis of the skin.